Abstract
Fusobacterium is enriched in colorectal cancer, but until now it has been unclear whether these bacteria drive tumorigenesis. A recent study shows that colorectal cancer cells take their microbiomes with them as they metastasize—and that targeting Fusobacterium with antibiotics reduces tumor growth in mice xenografts.
In 2011, two independent research groups reported enrichment of Fusobacterium species in colorectal carcinomas. Since then, scientists have wondered about the presence of these bacteria in colorectal cancer. Recently, one of the groups involved in the original discovery reported a new piece of the puzzle: When colorectal tumors metastasize, they bring Fusobacterium along—and when antibiotics are used to reduce Fusobacterium levels in mice with colorectal cancer xenografts, their tumors grow at a slower rate.
To study the colorectal cancer microbiome, researchers examined 112 paired samples of primary tumors and liver metastases. “Bacterial culture and sequencing tells us that the original cancer and the metastasis contain the same bacteria,” says Susan Bullman, PhD, of Dana-Farber Cancer Institute in Boston, MA, and lead author of the study. “This suggests that the tumor microbiota are intrinsic and essential components of the cancer microenvironment.”
The most prevalent bacterium was Fusobacterium nucleatum, an oral bacterium known for its role in periodontal disease, but the colorectal cancer microbiome also included Bacteroides, Prevotella, and Selenomonas species. However, the microbial resemblance between primary and metastatic tumors held only if Fusobacterium was present. When primary colorectal cancers had low or undetectable levels of Fusobacterium, the bacterial sequences found in metastases showed little similarity to those in their parent tumors.
The colorectal cancer microbiome persisted when Fusobacterium-positive colon cancers were used to create mouse xenografts. Using culturing and qPCR, the team showed that “Fusobacterium is still present in xenografts transplanted through many generations in mice,” says Bullman.
This allowed the researchers to test the effects of lowering tumors' Fusobacterium load with antibiotics. When they administered metronidazole to mice with Fusobacterium-positive xenografts, cancer cell proliferation and tumor growth slowed significantly relative to that observed in untreated mice or mice treated with an antibiotic ineffective against Fusobacterium. These results suggest that the bacteria could promote tumor growth and metastasis in humans as well—and that reducing the Fusobacterium load might reign in tumor growth.
“The significance of this study is that Fusobacterium appears to be driving aspects of tumor generation and spread, not just coming along for the ride as passengers,” says Robert Holt, PhD, who is codirector of the BC Cancer Agency Immunotherapy Program at the BC Cancer Research Centre in Vancouver, Canada, and the leader of the second team that reported the presence of Fusobacterium in colorectal cancer.
On the basis of these results, Bullman says she and her colleagues are exploring how the tumor microbiota can be modulated to treat early- and late-stage Fusobacterium-associated colorectal cancer.
However, this will be a complicated undertaking. “What we need most is a way to target Fusobacterium selectively,” explains Holt. “Broad spectrum antibiotics such as metronidazole can totally change the microbial ecosystem. This is a concern because the gut microbiome is turning out to be very important for regulating the sensitivity of the immune system and facilitating the action of cancer immunotherapies.” –Kristin Harper